Brain fog is a common issue in clinic with many clients reporting poor memory and concentration, fatigue and an inability to focus. Although it may seem trivial to some it can have debilitating effect on work, family and social life and it is also an indication of impaired cognition.
Brain fog may be an early warning that cognitive function is under stress, and it is associated with conditions including depression anxiety and dementia. Therefore, it is important to identify the drivers, understand the physiological processes involved, and implement interventions to support mental clarity and optimal cognition.
In this blog we look at factors which contribute to brain fog as well as associated conditions, highlighting the most appropriate interventions for individuals.
Although brain fog may be common it is associated with many different triggers such as infections, in particular SARS-CoV2 (covid) (40 percent of long covid patients experience brain fog)1, depression, menopause, stress, poor sleep, cardiovascular disorders, insulin resistance and thyroid dysfunction not to mention digestive issues and chronic inflammation. Many of these impact the brain by one of two ways (or both). Either by a lack of available energy to the brain leading to reduced cellular function or by damage to brain tissue mainly due to overactivation of the immune system, creating inflammation.
The brain has a high level of metabolic activity therefore also has high levels of mitochondrial activity. Impaired energy delivery or mitochondrial function will affect the ability for brain tissue to function normally which can lead to brain fog.
Infections as a cause of brain fog
Many of the effects of covid19 infections on brain function are still under investigation however a gathering body of evidence suggests significant impact on mitochondrial function, microglial activation and neuroinflammation.1
During initial covid infection lung tissue is infected, and the alveoli of the lungs become damaged, reducing the ability to absorb oxygen, this places the body in a state of hypoxia (low blood levels of oxygen). The brain has a high level of metabolic activity and therefore cerebral tissues require an immediate and constant supply of oxygen. In hypoxic conditions, neurons with the highest oxygen demand become dysfunctional.2
When this happens here is an initial drop in the brain’s ability to produce energy leading to symptoms such as headaches, fatigue and brain fog. However, this can manifest further and become more chronic as it appears that the virus hijacks the mitochondrial genome, to improve viral replication this reducing the mitochondria’s ability to produce energy that is destined for the brain’s neuronal tissue leading to persistent neurological changes.2
Additionally, the presence of the viral infection stimulates the immune system leading to activation on microglia in the brain, this increases neuroinflammation which subsequently can result in damage to nerve tissue, but also the activated microglia carry out a cleaning process, by pruning nerve synapses.
Synaptic pruning is essential for the recovery from infection. However, one hypothesis, supported by a research group is that following infection by SARS-CoV-2, somehow the microglia become immunoreactive, and destroy more synapses than normal.3
Covid19 seems to have a high affinity for the brain4, however this may not be exclusive to covid and may explain the onset of chronic fatigue and depression, among others, which are triggered by other infectious agents. Although brain fog due to Covid19 infection is still being researched what is consistent is that mitochondrial dysfunction and inflammation play a significant role and therefore must be a target of therapeutic intervention.
Mitochondrial function and brain fog
Of all of the neuropathological changes observed in Alzheimer’s disease (AD), the loss of synapses correlates most strongly with cognitive decline5 and may also play a role in brain fog. Synaptic mitochondria play a potentially important role in synapse degeneration in AD. Optimising mitochondrial function is therefore important for supporting healthy cognition and mental clarity and may play a role in protecting against cognitive decline.
Nutrients that support chemical energy production by mitochondria:6,7
Thiamin (B1) – Co factor in the essential step which converts pyruvate in to acetyl CoA
Riboflavin (B2) – Also known as FAD, accepts electrons and donated to the electron transport chain (ETC) in order to produce ATP (energy)
Niacin (B3) – Also known as NADH (similar to FAD) accepts and donates electron to ETC in order to produce ATP.
Pantothenic Acid (B5) – carrier of Coenzyme A, essential for Acetyl CoA and therefore energy production
CoQ10 – utilised as a carrier in complex II of ETC. CoQ10 also has antioxidant properties and is found to be depleted in patients with Alzheimer’s disease.
Alpha Lipoic Acid – a coenzyme of pyruvate dehydrogenase and a-ketoglutarate; enzymes responsible for reactions involved in the breakdown of fat and carbohydrate within the mitochondria
Magnesium – binds to ATP and affects its structure making energy more easily available.
All of the above nutrients are directly involved in metabolic reactions which occur in the mitochondria in order to produce energy, any deficiencies of the above nutrients can affect the rate of energy production.
There are other nutrients that are not directly involved in the chemical pathways of metabolism but are however important for energy production and maintaining mitochondrial function such as;
L-Carnitine – plays a vital role in fatty acid metabolism, transporting fatty acids into the mitochondria to be converted into energy and again a deficiency can lead to reduce energy production.8
Omega 3 Fatty Acids – can be incorporated into the mitochondrial membrane, which aids fluidity of the membrane and therefore signalling. Omega 3 fatty acids are also very important for cell and mitochondrial membranes and hence their stability.9
We can also help to protect our mitochondria by ensuring that we are consuming adequate levels of antioxidants.
The antioxidant of particular importance for the mitochondria is glutathione which is our own intrinsic intracellular antioxidant.
Although we are able to manufacture our own glutathione10, when oxidative stress is in excess it can become overwhelmed or if nutrients that are required to manufacture it are deficient this can lead to reduced levels.
Nutrients that support production of glutathione are;7,10
Liposomal Glutathione – this bypasses degradation within the gut and is absorbed directly across the digestive lining and can cross the blood-brain barrier.
N-Acetyl Cysteine – regulates synthesis of and is an effective precursor to glutathione
Alpha Lipoic Acid – has the ability to induce enzymes required for glutathione synthesis
Selenium – constituent of glutathione.
Vitamin C – major intracellular antioxidant
Brain fog and inflammation
Brain fog is also strongly associated with neuroinflammation. Post covid brain fog may be triggered by over activation of microglial, triggering an immune response and hence inflammation.11
It is also known that dementia and cognitive decline is driven at least initially by inflammation within the brain. Therefore, attenuating inflammation is essential for cognition and will also support mitochondrial function, which can be damaged by over production of free radicals created by excessive inflammatory molecules.
Curcumin – studies have shown that curcumin with advanced delivery in nano systems, such as liposomal curcumin, can attenuate neuroinflammation. Proposed therapeutic mechanism for this include, blocking inflammation by modulating endoplasmic reticulum stress and neutralising free radicals, it may also help protect against the effects of covid by inhibiting SARS-CoV-2 by delivery of curcumin to bind to the S-protein, ACE2 receptor.12 In addition, curcumin has been shown to Cox-2 enzymes which produce inflammatory prostaglandins as well as the NLRP3 inflammasome.13
Omega 3 fatty acids – support anti-inflammatory pathways via the production of anti-inflammatory prostaglandins. One study looking at patients with chemotherapy induced brain fog has shown that that a diet rich in long-chain, marine-derived omega-3 fatty acids and low in added sugars may be an ideal pattern for preventing or alleviating neuroinflammation and oxidative stress, thereby protecting neurones.14
NAC– an antioxidant with a role in attenuating pathophysiological processes associated with cognitive disorders including oxidative stress, apoptosis, mitochondrial dysfunction, neuroinflammation and glutamate and dopamine dysregulation. A systematic review found favourable evidence for the use of NAC in several psychiatric and neurological disorders, particularly autism, Alzheimer’s disease, bipolar disorder, depression, obsessive-compulsive disorder, schizophrenia, drug-induced neuropathy and progressive myoclonic epilepsy.15
Quercetin – has been demonstrated to prevent neuronal injury via inhibition of oxidative stress mediated inflammation (via NLRP3 inflammasome activation) in microglia through promoting mitophagy (breakdown of mitochondria, particularly those which are dysfunctional), which provides a potential novel therapeutic strategy for neuroinflammation-related diseases.16
It is essential to consider the impact of infections and inflammation on the ability of mitochondria and cells to function when it comes to cognitive impairment and utilise appropriate interventions. It is also essential to consider the availability of tropic support from nutrients and hormones. Therefore, we also need to consider the nutrition gap, digestive system, cardiovascular function and the endocrine system. This is discussed in our blog: Trophic Support for Cognitive Impairment
- Brain fog is common but it’s aetiology is unclear and may be due to multiple dysfunctions
- Studies on long covid have allowed us to understand further the impacts on cognitive function and mechanisms by which brain fog can occur.
- Brain fog associated with long covid has been shown to be due to the virus’s effect on oxygen delivery to the brain as well as affecting the mitochondria’s ability to produce energy as well as increasing neuroinflammation and therefore damage to tissue.
- Supporting energy delivery to the brain, mitochondrial function and reducing inflammation is essential
- Mitochondria are susceptible to oxidative stress and therefore including antioxidants such as N-acetyl cysteine, CoQ10, glutathione and alpha lipoic acid are important for protection of the mitochondria.
- Nutrients that support energy production by the mitochondria include B vitamins, CoQ10, L-carnitine and omega 3 fatty acids.
- Studies have shown that phytonutrients such as quercetin and curcumin as well as N-acetyl cysteine and omega 3 fatty acids can attenuate neuroinflammation by supporting anti-inflammatory pathways as well as acting as antioxidants.
- Stefano GB, Ptacek R, Ptackova H, Martin A, Kream RM. Selective Neuronal Mitochondrial Targeting in SARS-CoV-2 Infection Affects Cognitive Processes to Induce ‘Brain Fog’ and Results in Behavioral Changes that Favor Viral Survival. Med Sci Monit. 2021;27:e930886-1. doi:10.12659/MSM.930886
- Stefano GB, Ptacek R, Ptackova H, Martin A, Kream RM. Selective Neuronal Mitochondrial Targeting in SARS-CoV-2 Infection Affects Cognitive Processes to Induce “Brain Fog” and Results in Behavioral Changes that Favor Viral Survival. Med Sci Monit. 2021;27. doi:10.12659/MSM.930886
- Samudyata, Oliveira AO, Malwade S, et al. SARS-CoV-2 promotes microglial synapse elimination in human brain organoids. Mol Psychiatry. 2022;27(10):3939-3950. doi:10.1038/S41380-022-01786-2
- Long COVID: Brain fog | Long-term effects of COVID-19. Accessed June 1, 2023.
- Pickett EK, Rose J, McCrory C, et al. Region-specific depletion of synaptic mitochondria in the brains of patients with Alzheimer’s disease. Acta Neuropathol. 2018;136(5):747. doi:10.1007/S00401-018-1903-2
- Depeint F, Bruce WR, Shangari N, Mehta R, O’Brien PJ. Mitochondrial function and toxicity: Role of the B vitamin family on mitochondrial energy metabolism. Chem Biol Interact. 2006;163(1-2):94-112. doi:10.1016/j.cbi.2006.04.014
- Bland J et al. Textbook of Functional Medicine.; 2008.
- Ferreira GC, McKenna MC. L-Carnitine and Acetyl-L-carnitine Roles and Neuroprotection in Developing Brain. Neurochem Res. 2017;42(6):1661-1675. doi:10.1007/S11064-017-2288-7
- Al-Gubory KH. Mitochondria: omega-3 in the route of mitochondrial reactive oxygen species. Int J Biochem Cell Biol. 2012;44(9):1569-1573. doi:10.1016/J.BIOCEL.2012.06.003
- Averill-Bates DA. The antioxidant glutathione. Vitam Horm. 2023;121:109-141. doi:10.1016/BS.VH.2022.09.002
- Theoharides TC, Cholevas C, Polyzoidis K, Politis A. Long‐COVID syndrome‐associated brain fog and chemofog: Luteolin to the rescue. Biofactors. 2021;47(2):232. doi:10.1002/BIOF.1726
- Akanchise T, Angelova A. Potential of Nano-Antioxidants and Nanomedicine for Recovery from Neurological Disorders Linked to Long COVID Syndrome. Antioxidants (Basel). 2023;12(2). doi:10.3390/ANTIOX12020393
- Sun Y, Liu W, Zhang H, et al. Curcumin Prevents Osteoarthritis by Inhibiting the Activation of Inflammasome NLRP3. Journal of Interferon and Cytokine Research. 2017;37(10):449-455. doi:10.1089/jir.2017.0069
- Orchard TS, Gaudier-Diaz MM, Weinhold KR, Courtney DeVries A. Clearing the fog: a review of the effects of dietary omega-3 fatty acids and added sugars on chemotherapy-induced cognitive deficits. Breast Cancer Res Treat. 2017;161(3):391-398. doi:10.1007/S10549-016-4073-8
- Deepmala, Slattery J, Kumar N, et al. Clinical trials of N-acetylcysteine in psychiatry and neurology: A systematic review. Neurosci Biobehav Rev. 2015;55:294-321. doi:10.1016/J.NEUBIOREV.2015.04.015
- Han X, Xu T, Fang Q, et al. Quercetin hinders microglial activation to alleviate neurotoxicity via the interplay between NLRP3 inflammasome and mitophagy. Redox Biol. 2021;44. doi:10.1016/J.REDOX.2021.102010
If you have questions regarding the topics that have been raised, or any other health matters, please do contact our team of Nutritional Therapists.
Last updated on 28th July 2023 by cytoffice